Reparixin in Pancreatic Islet Transplantation

• Sponsor: Dompé Farmaceutici S.p.A (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01220856
• Collaborator: (none)
• Enrollment: 9
• Locations: 2
• Arms: 2
• Actual Duration (Months): 33.1
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Inhibition of CXCL8 activity might represent a relevant therapeutic target to prevent injury occurring after pancreatic islet transplantation. Reparixin is a novel and specific inhibitor of CXCL8. This study is designed to explore the efficacy of reparixin in preventing graft dysfunction after islet transplantation in type 1 diabetes patients (T1D).

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Islet Transplantation in Type 1 Diabetes Mellitus	Drug: Reparixin	Phase 2

Detailed Description

Pancreatic islet transplantation has become a feasible option in the treatment of T1D which offers advantages over whole pancreas transplantation. However to date insulin independence can be obtained in most cases only after the patient has received repeated infusions from several donors. A non-specific immune response, mediated predominantly by innate inflammatory processes, coupled with specific cellular immune responses, possibly promoted by early inflammation, play a major role in the loss of transplanted islets from the liver. PMNs have been found to be the predominant cell types infiltrating in vitro the islets. In this regard, CXCL8 has been shown to be expressed by human islets and could play a crucial role in triggering the inflammatory reaction. Thus, CXCL8 might represent a relevant therapeutic target to prevent early graft failure. The efficacy of reparixin in improving graft outcome in mice models of intrahepatic islet transplantation, as well as the safety shown in human phase 1 and 2 studies, provide a rationale for a clinical study aimed at evaluating the effect of reparixin in preventing graft dysfunction after islet transplantation in T1D patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Multicenter, Randomized, Open Label, Parallel Assignment, Pilot Study to Assess the Efficacy and Safety of Reparixin Following Islet Transplantation in Patients With Type 1 Diabetes Mellitus
• Actual Study Start Date: Jul 28, 2010
• Actual Primary Completion Date: Apr 30, 2013
• Actual Study Completion Date: Apr 30, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Reparixin Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description.	Drug: Reparixin; Reparixin + immunosuppression; Other Names: REP
No Intervention: No experimental intervention Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.

Outcome Measures

Primary Outcome Measures

1. The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5 [day 75 +/- 5 post-transplant]

   Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: HbA1c level of less than 7%; glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period); glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).

Other Outcome Measures

1. The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant [up to one year after the transplant]

   Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: HbA1c level of less than 7%; glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period); glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).

2. Time to Achieve Insulin-independence After the Transplant 2 [up to 1 year after transplant 2]

   Time to achieve insulin-independence after the transplant was defined as the number of days between islet infusion and onset of insulin-independence. This was calculated as: date of onset of insulin-independence minus the islet infusion date.

3. Total Time of Insulin Independence After the Transplant [up to 1 year after transplant 2]

   Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence. Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days.

4. Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels [Months 1, 3, 6, 12 post-transplant]

   Daily insulin requirement was calculated as the average requirement over the previous week (seven days).

5. Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels [Months 1, 3, 6, 12 post-transplant]

   Daily insulin requirement was calculated as the average requirement over the previous week (seven days).

6. Absolute Change in Fasted HbA1c From Pre-transplant Levels [Months 1, 3, 6, 12 post-transplant]

   The absolute change between the time-point value and baseline value.

7. Percentage Change in Fasted HbA1c From Pre-transplant Levels [Months 1, 3, 6, 12 post-transplant]

   The absolute percentage between the time-point value and baseline value.

8. The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness [Months 1, 3, 6, 12 post-transplant]

   Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as "hypoglycemia unawareness".

9. Number of Participants With Adverse Events by Severity and With Serious Adverse Events [up to 1 year after transplant]

   Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant. A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.

10. AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant [-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant]

    Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.

11. AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant [-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant]

    C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.

12. AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant [-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant]

    Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.

13. AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1 [-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant]

    For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated. AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg).

14. The Percentage of Patients Free of Severe Hypoglycaemic Events [Months 1, 3, 6, 12 post-transplant]

    A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.

15. Beta-cell Function as Assessed by Beta-score [Months 1, 3, 6, 12 post-transplant]

    The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function. Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function.

16. Beta-cell Function as Assessed by TEF/IEQ/kg Ratio [At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2]

    The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets.

17. Serum Level of Alanine Amino Transferase (ALT) [Pre-transplant and at days 1-7 and months 1 and 3 post-transplant]

    ALT is commonly measured clinically as part of liver function tests.

18. Serum Level of Aspartate Amino Transferase (AST) [Pre-transplant and at days 1-7 and months 1 and 3 post-transplant]

    AST is commonly measured clinically as part of liver function tests.

19. Change From Pre-transplant in Cytokine Levels - CXCL8 [6, 12, 24, 72, 120, and 168 hours post-transplant 1]

    Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).

20. Change From Pre-transplant in Cytokine Levels - CXCL1 [6, 12, 24, 72, 120, and 168 hours post-transplant 1]

    Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL1 (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).

21. Change From Pre-transplant in Cytokine Levels - IL-6 [6, 12, 24, 72, 120, and 168 hours post-transplant 1]

    Time course of inflammatory chemokines/cytokines as assessed by serum levels of interleukin 6 (IL-6) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• Ages 18-65 years, inclusive.

• Patients eligible for pancreatic islet transplantation based on local accepted practice and guidelines. This includes at least: a)clinical history compatible with T1D with insulin-dependence for >5 years; b) undetectable stimulated (arginine or MMTT) C-peptide levels (<0.3 ng/mL) in the 12 months before transplant. Sites will comply with any additional or more stringent criteria locally accepted, as per centre practice.

• Patients with adequate renal reserve as per calculated creatinine clearance (CLcr) > 60 mL/min according to the Cockcroft-Gault formula (1976).

• Planned intrahepatic islet transplantation alone from a non-living donor with brain death.

• Planned infusion of 4000 to 7000 islet equivalent (IEQ)/kg body weight.

• Patients willing and able to comply with the protocol procedures for the duration of the study, including scheduled follow-up visits and examinations.

• Patients given written informed consent, prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.

Exclusion criteria:

• Recipients of any previous transplant, except from recipients of a previous pancreatic islet transplantation that has failed, are off immunosuppression since at least 1 year and have negative anti-HLA.

• Recipients of islet from a non-heart beating donor.

• A body mass index >30 kg/m2 or patient weight <45 kg.

• Pre-transplant average daily insulin requirement >1 IU/kg/day.

• Pre-transplant HbA1c >11%.

• Patients with hepatic dysfunction as defined by increased ALT/AST > 3 x ULN and increased total bilirubin > 3mg/dL [>51.3 micromol/L]).

• Patients who receive treatment for a medical condition requiring chronic use of systemic steroids.

• Treatment with any anti-diabetic medication other than insulin within 4 weeks of transplant.

• Use of any investigational agent within 4 weeks of enrolment.

• Hypersensitivity to:

• ibuprofen or to more than one non steroidal anti-inflammatory drug

• medications belonging to the class of sulfonamides, such as sulfamethazine, sulfamethoxazole, sulfasalazine, nimesulide or celecoxib.

• Pregnant or breast-feeding women; unwillingness to use effective contraceptive measures (females and males).

Sites will comply with any additional exclusion criteria locally accepted, as per centre practice.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital Carl Gustav Carus Dresden	Dresden		Germany	01307
2	Ospedale San Raffaele	Milan		Italy	20132

Sponsors and Collaborators

• Dompé Farmaceutici S.p.A

Investigators

• Principal Investigator: Lorenzo Piemonti, MD, Fondazione Centro San Raffaele del Monte Tabor - Milan; Italy
• Principal Investigator: Barbara Ludwig, MD, University Hospital Carl Gustav Carus - Dresden; Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dompé Farmaceutici S.p.A
• ClinicalTrials.gov Identifier: NCT01220856
• Other Study ID Numbers: REP0110; 2010-019424-31
• First Posted: Oct 14, 2010
• Last Update Posted: Mar 11, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Dompé Farmaceutici S.p.A: Islet transplantation; Type 1 diabetes mellitus
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1

Study Results

Participant Flow

Recruitment Details	A total of 9 patients were enrolled into the study; 6 were randomized to reparixin and 3 to the control group. All in the control group and 2 in the reparixin group were withdrawn after Transplant 1 due to graft loss. 4 in the reparixin group received Transplant 2. Thereafter, 1 was withdrawn due to graft loss. 1 was lost to follow-up.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Period Title: Overall Study
STARTED	6	3
COMPLETED	2	0
NOT COMPLETED	4	3

Baseline Characteristics

Arm/Group Title	Reparixin	No Experimental Intervention	Total
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.	Total of all reporting groups
Overall Participants	6	3	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 100%	3 100%	9 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.2 (8.8)	48.0 (7.0)	46.8 (7.9)
Sex: Female, Male (Count of Participants)
Female	3 50%	2 66.7%	5 55.6%
Male	3 50%	1 33.3%	4 44.4%
Region of Enrollment (participants) [Number]
Italy	6 100%	3 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Insulin-independent Patients Following Single Infusion Islet Cell Transplantation at Day 75 +/- 5
Description	Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: HbA1c level of less than 7%; glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period); glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).
Time Frame	day 75 +/- 5 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Number [percentage of patients]	0	0

2. Other Pre-specified Outcome

Title	The Percentage of Insulin-independent Patients Following Islet Cell Transplantation up to One Year After the Last Transplant
Description	Insulin-independence was defined as freedom from the need to take exogenous insulin for 14 or more consecutive days, with adequate glycemic control, as defined by: HbA1c level of less than 7%; glucose level after an overnight fast not exceeding 140 mg/dL (7.8 mmol/L) more than 3 times a week (based on measuring capillary glucose level a minimum of 7 times in a 7-day period); glucose level not exceeding 2-hour postprandial levels of 180 mg/dL (10 mmol/L) more than 4 times a week (based on measuring capillary glucose level a minimum of 21 times in a 7-day period).
Time Frame	up to one year after the transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
transplant 1	0	0
transplant 2	50

3. Other Pre-specified Outcome

Title	Time to Achieve Insulin-independence After the Transplant 2
Description	Time to achieve insulin-independence after the transplant was defined as the number of days between islet infusion and onset of insulin-independence. This was calculated as: date of onset of insulin-independence minus the islet infusion date.
Time Frame	up to 1 year after transplant 2

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	3	0
Mean (Standard Deviation) [days]	66.3 (73.7)

4. Other Pre-specified Outcome

Title	Total Time of Insulin Independence After the Transplant
Description	Total time of insulin-independence after the transplant. This was defined as the number of days between the onset and loss of insulin-independence and was calculated as the date of loss of insulin-independence minus the date of onset of insulin-independence. Of the 3 patients who achieve insulin-independence after transplant 2, only 2 remained insulin-independent up to 1 year and the mean (SD) total time of insulin-independence after the second transplant was 276 (96.2) days with a range between 208 and 344 days.
Time Frame	up to 1 year after transplant 2

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	2	0
Mean (Standard Deviation) [total number of days]	276.0 (96.2)

5. Other Pre-specified Outcome

Title	Absolute Change in Average Daily Insulin Requirements From Pre-transplant Levels
Description	Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
Time Frame	Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	-0.3 (0.3)	0.1 (0.1)
Month 3 (transplant 1)	-0.3 (0.2)
Month 6 (transplant 1)	-0.2 (0.0)
Month 1 (transplant 2)	-0.6 (0.2)
Month 3 (transplant 2)	-0.6 (0.3)
Month 6 (transplant 2)	-0.5 (0.4)
Month 12 (transplant 2)	-0.7 (0.4)

6. Other Pre-specified Outcome

Title	Percentage Change in Average Daily Insulin Requirements From Pre-transplant Levels
Description	Daily insulin requirement was calculated as the average requirement over the previous week (seven days).
Time Frame	Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	-41.9 (39.9)	16.4 (20.2)
Month 3 (transplant 1)	-50.3 (24.4)
Month 6 (transplant 1)	-32.0 (8.9)
Month 1 (transplant 2)	-90.8 (11.3)
Month 3 (transplant 2)	-88.7 (17.8)
Month 6 (transplant 2)	-81.8 (36.5)
Month 12 (transplant 2)	-100.0 (0.0)

7. Other Pre-specified Outcome

Title	Absolute Change in Fasted HbA1c From Pre-transplant Levels
Description	The absolute change between the time-point value and baseline value.
Time Frame	Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	-1.53 (0.49)	-0.87 (0.40)
Month 3 (transplant 1)	-2.90 (0.74)
Month 6 (transplant 1)	-1.87 (0.60)
Month 1 (transplant 2)	-3.15 (0.57)
Month 3 (transplant 2)	-3.10 (0.76)
Month 6 (transplant 2)	-3.05 (1.03)
Month 12 (transplant 2)	-3.65 (0.92)

8. Other Pre-specified Outcome

Title	Percentage Change in Fasted HbA1c From Pre-transplant Levels
Description	The absolute percentage between the time-point value and baseline value.
Time Frame	Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	-16.7 (4.5)	-11.2 (5.4)
Month 3 (transplant 1)	-30.3 (7.9)
Month 6 (transplant 1)	-19.7 (7.2)
Month 1 (transplant 2)	-32.8 (5.9)
Month 3 (transplant 2)	-32.2 (7.4)
Month 6 (transplant 2)	-31.6 (10.1)
Month 12 (transplant 2)	-37.4 (9.2)

9. Other Pre-specified Outcome

Title	The Percentage of Patients Free of Hypoglycaemic Events With Reduced Awareness
Description	Reduced awareness is defined as a reduced ability to recognize symptoms of hypoglycemia, sometimes referred to as "hypoglycemia unawareness".
Time Frame	Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
month 1 (transplant 1)	100	100
month 3 (transplant 1)	100
month 6 (transplant 1)	100
month 1 (transplant 2)	100
month 3 (transplant 2)	100
month 6 (transplant 2)	100
month 12 (transplant 2)	100

10. Other Pre-specified Outcome

Title	Number of Participants With Adverse Events by Severity and With Serious Adverse Events
Description	Safety was assessed by monitoring the incidence and severity of adverse events (AEs) and serious AEs (SAEs) throughout the study up to 1 year after last transplant. A serious adverse event is an adverse reaction that results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a birth defect.
Time Frame	up to 1 year after transplant

Outcome Measure Data

Analysis Population Description

Safety Population: all patients who were randomized into the study.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
TEAE mild	5 83.3%	2 66.7%
TEAE moderate	6 100%	2 66.7%
TEAE severe	3 50%	1 33.3%
SAE	3 50%	1 33.3%

11. Other Pre-specified Outcome

Title	AUC (-10 to 120 Minutes Post-dose) of Glucose Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
Description	Glucose level reflects the metabolic control. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.
Time Frame	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1, transplant 1	318.9 (155.1)	308.3 (105.4)
Month 3, transplant 1	235.0 (77.6)
Month 6, transplant 1	277.2 (59.9)
Month 1, transplant 2	162.5 (36.3)
Month 3, transplant 2	171.2 (58.1)
Month 6, transplant 2	184.1 (74.4)
Month 12, last transplant	123.7 (18.3)

12. Other Pre-specified Outcome

Title	AUC (-10 to 120 Minutes Post-dose) of C-peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
Description	C-peptide level is an indirect measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.
Time Frame	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	0.951 (0.875)	0.200 (0.000)
Month 3 (transplant 1)	1.789 (1.059)
Month 6 (transplant 1)	1.426 (1.114)
Month 1 (transplant 2)	3.302 (1.661)
Month 3 (transplant 2)	2.488 (2.038)
Month 6 (transplant 2)	2.531 (1.831)
Month 12 (last transplant)	4.042 (1.683)

13. Other Pre-specified Outcome

Title	AUC (-10 to 120 Minutes Post-dose) of Insulin Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 and 12 Months Post-transplant
Description	Insulin level is a direct measure of pancreatic beta-cell function. The MMTT was performed after an overnight fast, at baseline (within 1 week prior to randomization), and at each of the following timepoints. AUC was calculated using the trapezoidal rule.
Time Frame	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	19.08 (15.72)	7.58 (2.91)
Month 3 (transplant 1)	28.25 (33.43)
Month 6 (transplant 1)	13.41 (7.81)
Month 1 (transplant 2)	20.99 (11.89)
Month 3 (transplant 2)	22.85 (23.07)
Month 6 (transplant 2)	19.97 (16.40)
Month 12 (transplant 2)	36.04 (13.83)

14. Other Pre-specified Outcome

Title	AUC(-10 to 120 Min Post Dose)/IEQ/kg for C Peptide Derived From Mixed Meal Tolerance Test (MMTT) at 1, 3, 6 Months Post-transplant 1
Description	For Transplant 1 (patients on reparixin), the mean C-Peptide AUC (derived from the MMTT) corrected by IEQ/kg values were calculated. AUC was calculated using the trapezoidal rule and normalized by the actual number of islet equivalents (IEQ) per kilo infused (IEQ/kg).
Time Frame	-10 to 120 Minutes Post-dose at Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	0.193 (0.158)	0.044 (0.004)
Month 3 (transplant 1)	0.366 (0.158)
Month 6 (transplant 1)	0.341 (0.265)

15. Other Pre-specified Outcome

Title	The Percentage of Patients Free of Severe Hypoglycaemic Events
Description	A severe hypoglycemic event is defined as an event with one of the following symptoms: "memory loss, confusion, uncontrollable behavior, irrational behavior, unusual difficulty in awakening, suspected seizure, seizure, loss of consciousness, or visual symptoms", in which the subject was unable to treat him/herself and which was associated with either a blood glucose level <54mg/dL or prompt recovery after oral carbohydrate, i.v. glucose, or glucagon administration.
Time Frame	Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
month 1 (transplant 1)	100	100
month 3 (transplant 1)	100
month 6 (transplant 1)	100
month 1 (transplant 2)	100
month 3 (transplant 2)	100
month 6 (transplant 2)	100
month 12 (transplant 2)	100

16. Other Pre-specified Outcome

Title	Beta-cell Function as Assessed by Beta-score
Description	The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function. Beta score is a composite scoring system based on fasting plasma glucose values, HbA1c, insulin independence or use of insulin/OHAs, and the determination of stimulated C-peptide levels. Normal values are given a score of 2, intermediate values merit a score of 1, and clearly abnormal values garner no points. Thus, a perfect score is 8, and a score of 0 indicates absolute absence of beta-cell function.
Time Frame	Months 1, 3, 6, 12 post-transplant

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1, transplant 1	1.83 (1.17)	1.33 (1.53)
Month 3, transplant 1	3.75 (1.26)
Month 6, transplant 1	1.67 (1.53)
Month 1, transplant 2	5.25 (1.50)
Month 3, transplant 2	4.75 (1.89)
Month 6, transplant 2	4.75 (2.63)
Month 12, transplant 2	6.50 (0.71)

17. Other Pre-specified Outcome

Title	Beta-cell Function as Assessed by TEF/IEQ/kg Ratio
Description	The TEF/IEQ/kg ratio is a parameter to assess transplant efficiency corrected by the number of transplanted islets.
Time Frame	At months 1, 3, 6 after transplant 1 and months 1,3, 6, and 12 after transplant 2

Outcome Measure Data

Analysis Population Description

Efficacy Population: All patients who were randomized and received the transplant were included in the efficacy population. This population was based on the treatment randomized, regardless of the treatment actually received.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Month 1 (transplant 1)	111.9 (64.1)	13.6 (49.6)
Month 3 (transplant 1)	176.6 (105.0)
Month 6 (transplant 1)	121.1 (30.0)
Month 1 (transplant 2)	1.143 (0.278)
Month 3 (transplant 2)	1.133 (0.336)
Month 6 (transplant 2)	1.100 (0.407)
Month 12 (transplant 2)	1.320 (0.212)

18. Other Pre-specified Outcome

Title	Serum Level of Alanine Amino Transferase (ALT)
Description	ALT is commonly measured clinically as part of liver function tests.
Time Frame	Pre-transplant and at days 1-7 and months 1 and 3 post-transplant

Outcome Measure Data

Analysis Population Description

Safety population: all patients who were randomized into the study.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Pre-transplant 1	23.0 (9.0)	28.7 (22.9)
Day 1 post-transplant 1	27.5 (8.7)	24.7 (18.6)
Day 2 post-transplant 1	26.3 (9.3)	36.3 (29.7)
Day 3 post-transplant 1	29.7 (9.7)	46.3 (34.9)
Day 4 post-transplant 1	38.5 (9.0)	64.7 (23.0)
Day 5 post-transplant 1	63.7 (21.9)	98.0 (33.2)
Day 6 post-transplant 1	86.0 (34.0)	108.3 (34.4)
Day 7 post-transplant 1	114.6 (56.4)	108.3 (45.7)
Month 1 (transplant 1)	25.8 (7.7)	29.7 (28.9)
Month 3 (transplant 1)	25.0 (8.7)
Pre-transplant 2	18.5 (7.9)
Day 1 post-transplant 2	24.8 (10.8)
Day 2 post-transplant 2	22.8 (9.3)
Day 3 post-transplant 2	22.8 (7.5)
Day 4 post-transplant 2	28.8 (10.8)
Day 5 post-transplant 2	31.8 (11.7)
Day 6 post-transplant 2	31.8 (13.0)
Day 7 post-transplant 2	35.3 (12.1)
Month 1 (transplant 2)	28.0 (12.5)
Month 3 (transplant 2)	21.0 (3.6)

19. Other Pre-specified Outcome

Title	Serum Level of Aspartate Amino Transferase (AST)
Description	AST is commonly measured clinically as part of liver function tests.
Time Frame	Pre-transplant and at days 1-7 and months 1 and 3 post-transplant

Outcome Measure Data

Analysis Population Description

Safety population: all patients who were randomized into the study.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
Pre-transplant 1	22.3 (14.6)	20.0 (7.5)
Day 1 post-transplant 1	30.5 (12.1)	18.7 (7.4)
Day 2 post-transplant 1	22.3 (9.2)	27.3 (12.5)
Day 3 post-transplant 1	24.7 (12.8)	31.7 (13.4)
Day 4 post-transplant 1	31.8 (9.3)	49.0 (35.5)
Day 5 post-transplant 1	60.2 (28.7)	74.3 (26.6)
Day 6 post-transplant 1	64.2 (22.1)	64.3 (29.4)
Day 7 post-transplant 1	82.0 (43.4)	55.0 (29.7)
Month 1 (transplant 1)	15.5 (3.6)	17.7 (10.0)
Month 3 (transplant 1)	15.8 (5.0)
Pre-transplant 2	17.0 (6.2)
Day 1 post-transplant 2	33.0 (18.7)
Day 2 post-transplant 2	21.0 (7.0)
Day 3 post-transplant 2	21.5 (5.8)
Day 4 post-transplant 2	26.8 (9.7)
Day 5 post-transplant 2	28.5 (7.5)
Day 6 post-transplant 2	23.0 (8.8)
Day 7 post-transplant 2	25.3 (10.4)
Month 1 (transplant 2)	17.3 (3.3)
Month 3 (transplant 2)	13.7 (5.0)

20. Other Pre-specified Outcome

Title	Change From Pre-transplant in Cytokine Levels - CXCL8
Description	Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL8 (CXC ligand 8 [formerly interleukin (IL)-8]) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).
Time Frame	6, 12, 24, 72, 120, and 168 hours post-transplant 1

Outcome Measure Data

Analysis Population Description

Safety population: all patients who were randomized into the study.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
6 hours post-transplant	11.0 (14.4)	22.1 (19.0)
12 hours post-transplant	43.8 (45.5)	32.9 (43.3)
24 hours post-transplant	10.6 (21.8)	11.3 (2.1)
72 hours post-transplant	17.3 (12.0)	2.6 (8.5)
120 hours post-transplant	1.2 (8.0)	-2.2 (5.4)
168 hours post-transplant	-6.8 (5.0)	-2.8 (1.7)

21. Other Pre-specified Outcome

Title	Change From Pre-transplant in Cytokine Levels - CXCL1
Description	Time course of inflammatory chemokines/cytokines as assessed by serum levels of CXCL1 (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).
Time Frame	6, 12, 24, 72, 120, and 168 hours post-transplant 1

Outcome Measure Data

Analysis Population Description

Safety population: all patients who were randomized into the study.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
6 hours post-transplant	-12.5 (51.8)	-31.9 (31.0)
12 hours post-transplant	11.8 (72.4)	-16.8 (16.2)
24 hours post-transplant	1.4 (61.9)	-65.6 (127.0)
72 hours post-transplant	63.7 (40.7)	-51.9 (157.7)
120 hours post-transplant	8.7 (16.1)	-60.2 (130.6)
168 hours post-transplant	-10.7 (65.0)	-16.3 (88.7)

22. Other Pre-specified Outcome

Title	Change From Pre-transplant in Cytokine Levels - IL-6
Description	Time course of inflammatory chemokines/cytokines as assessed by serum levels of interleukin 6 (IL-6) (time frame: 0, 6, 12, 24, 72, 120, and 168 hours after islet infusion).
Time Frame	6, 12, 24, 72, 120, and 168 hours post-transplant 1

Outcome Measure Data

Analysis Population Description

Safety population: all patients who were randomized into the study.

Arm/Group Title	Reparixin	No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosuppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression	Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
Measure Participants	6	3
6 hours post-transplant	0.5 (4.0)	12.1 (10.6)
12 hours post-transplant	15.5 (20.6)	23.4 (27.9)
24 hours post-transplant	7.6 (10.7)	2.3 (7.5)
72 hours post-transplant	16.3 (13.5)	3.1 (13.3)
120 hours post-transplant	0.8 (5.2)	-5.6 (14.1)
168 hours post-transplant	-2.6 (3.2)	-5.5 (8.6)

Adverse Events

Time Frame	Through study completion, till follow-up (up to 1 year after the second islet infusion).
Arm/Group Title	Reparixin		No Experimental Intervention
Arm/Group Description	Reparixin + Immunosuppression Reparixin was administered at a dose of 2.772 mg/kg body weight/hour for 7 days (168 hours) at each transplant. It was administered as a continuous IV infusion into a (high-flow) central vein. Investigational Product infusion was to begin approximately 12 hours (range between 6 to 16 hours) before each pancreatic islet infusion was started. The Investigator identified the time to start study drug administration. Reparixin was given to all patients of this arm using the same dosing solution (reparixin 11.00 mg/mL), but the pump rate was adjusted to provide an infusion rate of approximately 0.25 mL/kg/hour. For immunosoppression regimen see the other arm description. Reparixin: Reparixin + immunosuppression		Immunosuppression only. Induction: First islet infusion: anti-thymocyte globulin (ATG), administered IV (central vein) at the dose of 1.5 mg/kg on Day -1, 0, 1, and 2 of islet infusion. The first ATG injection was preceded by a bolus IV injection of 500 mg methylprednisolone. Induction for the second islet infusion was to be administered per center practice. Maintenance: Mycophenolate mofetil (MMF), administered orally at the dose of 1 g twice a day, starting on Day -1 of the first islet infusion; Tacrolimus, administered orally starting on Day -1 of the first islet infusion at a dose of 0.087 mg/kg twice a day. Thereafter, dosing was to be targeted to blood trough levels of 8 to 10 ng/mL. Administration continued up to Month 3 after the first transplant. Rapamycin was to replace tacrolimus from Month 3 after the first transplant. It was to be administered orally at the starting dose of 0.1 mg/kg once a day, then targeted to a blood trough level of 10 to 12 ng/mL.
All Cause Mortality
	Reparixin		No Experimental Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/3 (0%)
Serious Adverse Events
	Reparixin		No Experimental Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		1/3 (33.3%)
Blood and lymphatic system disorders
Anemia	1/6 (16.7%)	1	0/3 (0%)	0
Gastrointestinal disorders
Diarrhea	2/6 (33.3%)	2	0/3 (0%)	0
Gastrointestinal hemorrhage	1/6 (16.7%)	1	0/3 (0%)	0
Nausea	1/6 (16.7%)	1	0/3 (0%)	0
Peritoneal hemorrhage	1/6 (16.7%)	1	0/3 (0%)	0
Vomiting	1/6 (16.7%)	1	0/3 (0%)	0
Injury, poisoning and procedural complications
Drug administration error	1/6 (16.7%)	1	0/3 (0%)	0
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/6 (16.7%)	1	0/3 (0%)	0
Renal and urinary disorders
Renal impairment	1/6 (16.7%)	1	0/3 (0%)	0
Vascular disorders
Hemorrhage	0/6 (0%)	0	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Reparixin		No Experimental Intervention
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		3/3 (100%)
Blood and lymphatic system disorders
Anaemia	2/6 (33.3%)	2	0/3 (0%)	0
Endocrine disorders
Hypothyroidism	1/6 (16.7%)	1	0/3 (0%)	0
Gastrointestinal disorders
Abdominal pain	2/6 (33.3%)	2	0/3 (0%)	0
Diarrhoea	4/6 (66.7%)	5	1/3 (33.3%)	1
Nausea	5/6 (83.3%)	5	1/3 (33.3%)	1
Stomatitis	2/6 (33.3%)	2	0/3 (0%)	0
Vomiting	3/6 (50%)	3	1/3 (33.3%)	1
General disorders
Infusion site pain	3/6 (50%)	3	1/3 (33.3%)	1
Oedema	1/6 (16.7%)	1	0/3 (0%)	0
Hepatobiliary disorders
Hepatic haemorrhage	1/6 (16.7%)	1	0/3 (0%)	0
Investigations
Blood bicarbonate decreased	1/6 (16.7%)	1	0/3 (0%)	0
Blood creatinine increased	1/6 (16.7%)	1	0/3 (0%)	0
Body temperature increased	0/6 (0%)	0	1/3 (33.3%)	1
C-reactive protein increased	0/6 (0%)	0	1/3 (33.3%)	1
Fibrin degradation product increased	0/6 (0%)	0	1/3 (33.3%)	1
Metabolism and nutrition disorders
Hypocalcaemia	2/6 (33.3%)	2	0/3 (0%)	0
Hypokalaemia	1/6 (16.7%)	2	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/6 (16.7%)	1	1/3 (33.3%)	1
Nervous system disorders
Headache	3/6 (50%)	3	1/3 (33.3%)	1
Neuralgia	0/6 (0%)	0	1/3 (33.3%)	1
Skin and subcutaneous tissue disorders
Acne	2/6 (33.3%)	2	0/3 (0%)	0
Erythema	4/6 (66.7%)	6	1/3 (33.3%)	1
Rash	0/6 (0%)	0	1/3 (33.3%)	2
Vascular disorders
Hypertension	1/6 (16.7%)	1	0/3 (0%)	0
Hypotension	2/6 (33.3%)	2	0/3 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.